Thomas Norton, MD, received his medical degree from Georgetown University School of Medicine and completed residency training in Internal Medicine at Georgetown University Hospital. He then became the Clinic Physician for the NIAID HIV clinic, where he treated HIV-infected patients enrolled in clinical trials. Through his involvement with translational studies, he developed an interest in clinical and basic HIV research. To pursue these interests, he did a fellowship in Infectious Diseases at the NYU School of Medicine. For the research portion of the fellowship, he joined the laboratory of Dr. Nathaniel Landau, a senior professor in the Department of Microbiology at NYU Langone Medical Center (NYULMC), where he developed the preliminary data on which the proposed project is based. After completing his fellowship, he became a junior faculty member in the Division of Infectious Diseases of the NYU School of Medicine Department of Medicine. He has presented his research at national conferences, and published in respected scientific journals. His goal is to become an independent, NIH-funded physician-scientist focused on the development of novel immunotherapeutics to treat HIV. He seeks NIH K08 funding to provide the training needed to advance his career towards independence. The NYU School of Medicine is a prominent academic biomedical research institute that provides a strong training environment to young investigators. The Institute is funded by NIH research and training grants and provides state of-the-art core facilities. Dr. Landau will serve as the primary mentor in Dr. Norton's research training. Dr. Nina Bhardwaj, a senior professor at the Icahn School of Medicine at Mount Sinai (ISMMS) in New York City, will serve as co-mentor. Dr. Landau is a retrovirologist who works on host restrictions to HIV-1 and the roles of lentivirus accessory proteins while Dr. Bhardwaj is an immunologist with expertise in dendritic cell (DC) biology and DC-based vaccines. The combined expertise of Drs. Landau and Bhardwaj will synergize to advance the project and provide perspectives on careers in clinical and basic science research. An advisory committee consisting of prominent physician-scientists with relevant expertise, Dan Littman (NYULMC), Ed Skolnik (NYULMC), and Benhur Lee (ISSM), will meet with Dr. Norton biannually to provide additional mentorship. They will provide scientific and career guidance by critically reviewing his research, advising on manuscript and grant preparations, and evaluating future research directions. To complement the mentorship plans in place, Dr. Norton will pursue a comprehensive training plan that includes graduate-level classes in Immunology, Virology, and Bioinformatics, regular attendance at seminars at NYULMC and surrounding research institutions, and speaking at local and national scientific symposia. This will strengthen his practical and theoretical foundation in basic and translational research and allow him to develop the expertise needed to run his own lab. During the K08-award Dr. Norton will devote a minimum of 75% effort to research and career development and the remainder to his clinical and teaching responsibilities at Bellevue Hospital Center. The project will develop a DC-based therapeutic vaccine to treat HIV-infected individuals. Infected individuals are subject to life-lon treatment with antiretroviral drugs. Cessation of treatment results in a rapid rebound of virus loads that is seeded by a long-lived reservoir of latently infected T cells. The project will develp a lentiviral-vector-based, DC-targeted therapeutic HIV-1 vaccine to address this problem. The approach is a two-pronged strategy that activates provirus expression in latently infected T cells and stimulates an immune response against infected cells to target them for lysis and diminish the size of the latent reservoir, with the goal of allowing patients to stop antiretroviral therapy Lentiviral vectors will be generated that express HIV-1 antigens such as mosaic Gag that is optimized for CTL epitopes. The vectors will co-express CD40 ligand to increase the antigen presentation activity of the transduced DCs and stimulate antigen-specific T cell responses. The vectors will be used to transduce DCs from uninfected and HIV-1-infected individuals in vitro. The ability of the transduced DCs to induce innate and adaptive immune responses will be determined using immunological assays. The ability of the transduced DCs to activate latent proviruses will be tested using a primary-T-cell latency model and resting CD4 T cells from HIV-infected patients on antiretroviral therapy. Development of this vaccine approach will have implications for many diseases in addition to HIV, where stimulation of an antigen-specific immune response is beneficial.